Chronic liver disease is suspected to be responsible for 5-11% of the deaths that occur among hemophiliacs. The frequency of hepatitis B virus (HBV) markers in this population has not changed appreciably since screening of donor blood for HBsAg became mandatory in 1975. While many hemophiliacs are believed to have non-A, non-B (NANB) hepatitis as the cause of their liver disease, active infection with HBV still accounts for a reasonable proportion of the cases. Recently, the discovery of a new viral agent, hepatitis delta virus (HDV), has enhanced our understanding of the immunopathogenesis of chronic liver disease. The unique characteristics of HDV is that it is dependent on HBV replication for its expression. Superinfection of hepatitis B patients with HDV often leads to severe and ultimately fatal disease. Because of this, there is a growing concern that HDV may be responsible for the development of more serious form of chronic liver disease seen in hemophiliacs with hepatitis B. Methods to remove or inactivate this virus from clotting factor concentrates, e.g. by heat-inactivation, apparently have not been successful. The long-term objectives and specific aims of this proposal are to determine the prevalence of HDV in a large cohort of hemophiliacs and to elucidate the role of HDV in the development and progression of liver disease in this population. Active HDV infection will be established by employing sensitive, noninvasive serologic techniques that have recently been developed, such as HDV RNA/cDNA probes to detect HDV RNA and an immunoblotting method to detect HDAg. These tests should avert the need for a liver biopsy to verify HDV infection. Longitudinal studies to monitor liver function, assess alterations in lymphocyte markers, and evaluate delayed type hypersensitivity reactions will help determine whether combined HBV and HDV infections are clinically more serious than infections associated with NANB hepatitis or HBV alone. The presence and physical state of HBV DNA in serum and peripheral blood mononuclear cells (PBMC) of hemophiliacs will be related to the detection of HDV in serum. Similarly, the study will determine whether the presence of PBMC-associated HBV DNA in some "HBV immune" patients is sufficient to permit replication of HDV. Finally, household members of hemophiliacs will be examined for evidence of HBV, HDV and NANB hepatitis infection in order to determine the risk of transmission of these agents in the home environment.